Dilated cardiomyopathy (DCM) is a heritable, genetically heterogeneous disorder causing congestive heart failure. Current medical therapy has minimal impact on prognosis and cardiac transplantation is the only definitive treatment for end-stage disease. The molecular and cellular mechanisms underlying DCM are poorly defined, but the importance of single gene defects in disease pathogenesis is becoming increasingly apparent. The objective of this study is to identify novel DCM genes by genetic linkage and mutational analyses. The first aim is to determine the chromosomal location of novel familial DCM genes. This will be accomplished by genome-wide genotyping and genetic linkage analyses in 3 large families with autosomal dominant DCM. Previously identified DCM genes have been excluded in these families. The second aim is to identify mutations in novel genes that cause familial DCM by linkage and sequence analyses of candidate genes mapping to DCM loci. Once novel genes for familial DCM are identified, the third aim will be to determine the role of these genes in a large cohort of unrelated patients with familial and sporadic DCM. High throughput DNA sequence analyses will be performed to identify additional inherited and de novo mutations. The long-term objectives of this work are to gain new insights into molecular mechanisms for heart failure and to improve prediction, prevention, and treatment of DCM.